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Cognitive control processes enable the suppression of automatic behaviors and the initiation of appropriate responses. The Stroop color naming task serves as a benchmark paradigm for understanding the neurobiological model of verbal cognitive control. Previous research indicates a predominant engagement of the prefrontal and premotor cortex during the Stroop task compared to reading. We aim to further this understanding by creating a dynamic atlas of task-preferential modulations of functional connectivity through white matter. Patients undertook word-reading and Stroop tasks during intracranial EEG recording. We quantified task-related high-gamma amplitude modulations at 547 nonepileptic electrode sites, and a mixed model analysis identified regions and timeframes where these amplitudes differed between tasks. We then visualized white matter pathways with task-preferential functional connectivity enhancements at given moments. Word reading, compared to the Stroop task, exhibited enhanced functional connectivity in inter- and intra-hemispheric white matter pathways from the left occipital-temporal region 350-600 ms before response, including the posterior callosal fibers as well as the left vertical occipital, inferior longitudinal, inferior fronto-occipital, and arcuate fasciculi. The Stroop task showed enhanced functional connectivity in the pathways from the left middle-frontal pre-central gyri, involving the left frontal u-fibers and anterior callosal fibers. Automatic word reading largely utilizes the left occipital-temporal cortices and associated white matter tracts. Verbal cognitive control predominantly involves the left middle frontal and precentral gyri and its connected pathways. Our dynamic tractography atlases may serve as a novel resource providing insights into the unique neural dynamics and pathways of automatic reading and verbal cognitive control., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In adults, individual differences in procedural learning (PL) are associated with white matter organization within the basal ganglia-cerebellar circuit. However, no research has examined whether this circuitry is related to individual differences in PL during childhood. Here, 28 children (M age  = 10.00 ± 2.31, 10 female) completed the serial reaction time (SRT) task to measure PL, and underwent structural magnetic resonance imaging (MRI). Fixel-Based Analysis was performed to extract specific measures of white matter fiber density (FD) and fiber cross-section (FC) from the superior cerebellar peduncles (SCP) and the striatal premotor tracts (STPMT), which underlie the fronto-basal ganglia-cerebellar system. These fixel metrics were correlated with the 'rebound effect' from the SRT task - a measure of PL proficiency which compares reaction times associated with generating a sequence, to random trials. While no significant associations were observed at the fixel level, a significant positive association was observed between average FD in the right SCP and the rebound effect, with a similar trend observed in the left SCP. No significant effects were detected in the STPMT. Our results indicate that, like in adults, microstructure of the basal ganglia-cerebellar circuit may explain individual differences in childhood PL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Telomere length (TL) is an important cellular marker of biological aging impacting the brain and heart. However, how it is related to the brain (e.g., cognitive function and neuroanatomic architecture), and how these relationships may vary by sex and reproductive status, is not well established. Here we assessed the association between leukocyte TL and memory circuitry regional brain volumes and memory performance in early midlife, in relation to sex and reproductive status. Participants (N = 198; 95 females, 103 males; ages 45-55) underwent structural MRI and neuropsychological assessments of verbal, associative, and working memory. Overall, shorter TL was associated with smaller white matter volume in the parahippocampal gyrus and dorsolateral prefrontal cortex. In males, shorter TL was associated with worse working memory performance and corresponding smaller white matter volumes in the parahippocampal gyrus, anterior cingulate cortex, and dorsolateral prefrontal cortex. In females, the impact of cellular aging was revealed over the menopausal transition. In postmenopausal females, shorter TL was associated with poor associative memory performance and smaller grey matter volume in the right hippocampus. In contrast, TL was not related to memory performance or grey and white matter volumes in any memory circuitry region in pre/perimenopausal females. Results demonstrated that shorter TL is associated with worse memory function and smaller volume in memory circuitry regions in early midlife, an association that differs by sex and reproductive status. Taken together, TL may serve as an early indicator of sex-dependent brain abnormalities in early midlife., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Human brain gray matter (GM) has usually been clustered into multiple functional networks. The white matter (WM) fiber bundles are known to interconnect these networks simultaneously, engaging in numerous cognitive functions. However, the exact interconnections between GM and WM are still unclear, whether functional signals in WM rewires GM community organization remains to be explored. In this study, we divided brain functional connections into three types by using edge-centric method, including intra-GM, intra-WM and GM-WM connections, and calculated the edge community evaluation indexes for quantifying GM community engagement. The results showed that the involvement of WM significantly enhanced community entropy in the heteromodal system, while the sensory-attention system remained barely changed. In addition, delta community entropy showed a significant correlation with clinical cognitive scale. Our results suggested that WM rewired GM community organization, enhancing the community engagement of brain regions in the heteromodal system. This involvement was observed to be disrupted in disease groups. Our study revealed that considering the functional signals of GM and WM simultaneously could better understand the brain's functional organization., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest relevant to this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

There is growing evidence that blood-oxygen-level-dependent (BOLD) activity in the white matter (WM) can be detected by functional magnetic resonance imaging (fMRI). However, the functional relevance and significance of WM BOLD signals remain controversial. Here we investigated whether 7T BOLD fMRI can reveal fine-scale functional organizations of a WM bundle. Population receptive field (pRF) analyses of the 7T retinotopy dataset from the Human Connectome Project revealed clear contralateral retinotopic organizations of two visual WM bundles: the optic radiation (OR) and the vertical occipital fasciculus (VOF). The retinotopic maps of OR are highly consistent with post-mortem dissections and diffusion tractographies, while the VOF maps are compatible with the dorsal and ventral visual areas connected by the WM. Similar to the grey matter (GM) visual areas, both WM bundles show over-representations of the central visual field and increasing pRF size with eccentricity. Hemodynamic response functions of visual WM were slower and wider compared with those of GM areas. These findings clearly demonstrate that WM BOLD at 7 Tesla is closely coupled with neural activity related to axons, encoding highly specific information that can be used to characterize fine-scale functional organizations of a WM bundle., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tractography enables identifying and evaluating the healthy and diseased brain's white matter pathways from diffusion-weighted magnetic resonance imaging data. As previous evaluation studies have reported significant false-positive estimation biases, recent microstructure-informed tractography algorithms have been introduced to improve the trade-off between specificity and sensitivity. However, a major limitation for characterizing the performance of these techniques is the lack of ground truth brain data. In this study, we compared the performance of two relevant microstructure-informed tractography methods, SIFT2 and COMMIT, by assessing the subject specificity and reproducibility of their derived white matter pathways. Specifically, twenty healthy young subjects were scanned at eight different time points at two different sites. Subject specificity and reproducibility were evaluated using the whole-brain connectomes and a subset of 29 white matter bundles. Our results indicate that although the raw tractograms are more vulnerable to the presence of false-positive connections, they are highly reproducible, suggesting that the estimation bias is subject-specific. This high reproducibility was preserved when microstructure-informed tractography algorithms were used to filter the raw tractograms. Moreover, the resulting track-density images depicted a more uniform coverage of streamlines throughout the white matter, suggesting that these techniques could increase the biological meaning of the estimated fascicles. Notably, we observed an increased subject specificity by employing connectivity pre-processing techniques to reduce the underlaying noise and the data dimensionality (using principal component analysis), highlighting the importance of these tools for future studies. Finally, no strong bias from the scanner site or time between measurements was found. The largest intraindividual variance originated from the sole repetition of data measurements (inter-run)., Competing Interests: Conflict of interest G.F.P., T.H., and T.K. are employees of Siemens Healthcare AG, Switzerland., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

A general linear model is widely used for analyzing fMRI data, in which the blood oxygenation-level dependent (BOLD) signals in gray matter (GM) evoked in response to neural stimulation are modeled by convolving the time course of the expected neural activity with a canonical hemodynamic response function (HRF) obtained a priori. The maps of brain activity produced reflect the magnitude of local BOLD responses. However, detecting BOLD signals in white matter (WM) is more challenging as the BOLD signals are weaker and the HRF is different, and may vary more across the brain. Here we propose a model-free approach to detect changes in BOLD signals in WM by measuring task-evoked increases of BOLD signal synchrony in WM fibers. The proposed approach relies on a simple assumption that, in response to a functional task, BOLD signals in relevant fibers are modulated by stimulus-evoked neural activity and thereby show greater synchrony than when measured in a resting state, even if their magnitudes do not change substantially. This approach is implemented in two technical stages. First, for each voxel a fiber-architecture-informed spatial window is created with orientation distribution functions constructed from diffusion imaging data. This provides the basis for defining neighborhoods in WM that share similar local fiber architectures. Second, a modified principal component analysis (PCA) is used to estimate the synchrony of BOLD signals in each spatial window. The proposed approach is validated using a 3T fMRI dataset from the Human Connectome Project (HCP) at a group level. The results demonstrate that neural activity can be reliably detected as increases in fMRI signal synchrony within WM fibers that are engaged in a task with high sensitivities and reproducibility., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Experience-dependent white matter plasticity offers new potential for rehabilitation-induced recovery after neurotrauma. This first-in-human translational experiment combined myelin water imaging in humans and genetic fate-mapping of oligodendrocyte lineage cells in mice to investigate whether downhill locomotor rehabilitation that emphasizes eccentric muscle actions promotes white matter plasticity and recovery in chronic, incomplete spinal cord injury (SCI). In humans, of 20 individuals with SCI that enrolled, four passed the imaging screen and had myelin water imaging before and after a 12-week (3 times/week) downhill locomotor treadmill training program (SCI + DH). One individual was excluded for imaging artifacts. Uninjured control participants (n = 7) had two myelin water imaging sessions within the same day. Changes in myelin water fraction (MWF), a histopathologically-validated myelin biomarker, were analyzed in a priori motor learning and non-motor learning brain regions and the cervical spinal cord using statistical approaches appropriate for small sample sizes. PDGFRα-CreER T2 :mT/mG mice, that express green fluorescent protein on oligodendrocyte precursor cells and subsequent newly-differentiated oligodendrocytes upon tamoxifen-induced recombination, were either naive (n = 6) or received a moderate (75 kilodyne), contusive SCI at T9 and were randomized to downhill training (n = 6) or unexercised groups (n = 6). We initiated recombination 29 days post-injury, seven days prior to downhill training. Mice underwent two weeks of daily downhill training on the same 10% decline grade used in humans. Between-group comparison of functional (motor and sensory) and histological (oligodendrogenesis, oligodendroglial/axon interaction, paranodal structure) outcomes occurred post-training. In humans with SCI, downhill training increased MWF in brain motor learning regions (postcentral, precuneus) and mixed motor and sensory tracts of the ventral cervical spinal cord compared to control participants (P < 0.05). In mice with thoracic SCI, downhill training induced oligodendrogenesis in cervical dorsal and lateral white matter, increased axon-oligodendroglial interactions, and normalized paranodal structure in dorsal column sensory tracts (P < 0.05). Downhill training improved sensorimotor recovery in mice by normalizing hip and knee motor control and reducing hyperalgesia, both of which were associated with new oligodendrocytes in the cervical dorsal columns (P < 0.05). Our findings indicate that eccentric-focused, downhill rehabilitation promotes white matter plasticity and improved function in chronic SCI, likely via oligodendrogenesis in nervous system regions activated by the training paradigm. Together, these data reveal an exciting role for eccentric training in white matter plasticity and sensorimotor recovery after SCI., (Copyright © 2021. Published by Elsevier Inc.)

Multiple studies have reported a significant dependence of the effective transverse relaxation rate constant (R 2 * ) and the phase of gradient-echo based (GRE) signal on the orientation of white matter fibres in the human brain. It has also been hypothesized that magnetic susceptibility, as obtained by single-orientation quantitative susceptibility mapping (QSM), exhibits such a dependence. In this study, we investigated this hypothesized relationship in a cohort of healthy volunteers. We show that R 2 * follows the predicted orientation dependence consistently across white matter regions, whereas the apparent magnetic susceptibility is related differently to fibre orientation across the brain and often in a complex non-monotonic manner. In addition, we explored the effect of fractional anisotropy measured by diffusion-weighted MRI on the strength of the orientation dependence and observed only a limited influence in many regions. However, with careful consideration of such an impact and the limitations imposed by the ill-posed nature of the dipole inversion process, it is possible to study magnetic susceptibility anisotropy in specific brain regions with a single orientation acquisition., Competing Interests: Declaration of Competing Interest None, (Copyright © 2021. Published by Elsevier Inc.)

Current views on the neural network subserving reading and its deficits in dyslexia rely largely on evidence derived from functional neuroimaging studies. However, understanding the structural organization of reading and its aberrations in dyslexia requires a hodological approach, studies of which have not provided consistent findings. Here, we adopted a whole brain hodological approach and investigated relationships between structural white matter connectivity and reading skills and phonological processing in a cross-sectional study of 44 adults using individual local connectome matrix from diffusion MRI data. Moreover, we performed quantitative anisotropy aided differential tractography to uncover structural white matter anomalies in dyslexia (23 dyslexics and 21 matched controls) and their correlation to reading-related skills. The connectometry analyses indicated that reading skills and phonological processing were both associated with corpus callosum (tapetum), forceps major and minor, as well as cerebellum bilaterally. Furthermore, the left dorsal and right thalamic pathways were associated with phonological processing. Differential tractography analyses revealed structural white matter anomalies in dyslexics in the left ventral route and bilaterally in the dorsal route compared to the controls. Connectivity deficits were also observed in the corpus callosum, forceps major, vertical occipital fasciculus and corticostriatal and thalamic pathways. Altered structural connectivity in the observed differential tractography results correlated with poor reading skills and phonological processing. Using a hodological approach, the current study provides novel evidence for the extent of the reading-related connectome and its aberrations in dyslexia. The results conform current functional neuroanatomical models of reading and developmental dyslexia but provide novel network-level and tract-level evidence on structural connectivity anomalies in dyslexia, including the vertical occipital fasciculus., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organization. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple "crossing" fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the "Fixel-Based Analysis" (FBA) framework, which implements bespoke solutions to this end. It has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to Fixel-Based Analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of all current FBA studies, categorized across a broad range of neuro-scientific domains, listing key design choices and summarizing their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the FBA framework, and outline some directions and future opportunities., (Copyright © 2021. Published by Elsevier Inc.)

Diffusion weighted imaging (DWI) is a widely recognized neuroimaging technique to evaluate the microstructure of brain white matter. The objective of this study is to establish an improved automated DWI marker for estimating white matter integrity and investigating ageing related cognitive decline. The concept of Wasserstein distance was introduced to help establish a new measure: difference in distribution functions (DDF), which captures the difference of reshaping one's mean diffusivity (MD) distribution to a reference MD distribution. This new DWI measure was developed using a population-based cohort (n=19,369) from the UK Biobank. Validation was conducted using the data drawn from two independent cohorts: the Sydney Memory and Ageing Study, a community-dwelling sample (n=402), and the Renji Cerebral Small Vessel Disease Cohort Study (RCCS), which consisted of cerebral small vessel disease (CSVD) patients (n=171) and cognitively normal controls (NC) (n=43). DDF was associated with age across all three samples and better explained the variance of changes than other established DWI measures, such as fractional anisotropy, mean diffusivity and peak width of skeletonized mean diffusivity (PSMD). Significant correlations between DDF and cognition were found in the UK Biobank cohort and the MAS cohort. Binary logistic analysis and receiver operator characteristic curve analysis of RCCS demonstrated that DDF had higher sensitivity in distinguishing CSVD patients from NC than the other DWI measures. To demonstrate the flexibility of DDF, we calculated regional DDF which also showed significant correlation with age and cognition. DDF can be used as a marker for monitoring the white matter microstructural changes and ageing related cognitive decline in the elderly., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Ultra-High Field (UHF) MRI provides a significant increase in Signal-to-Noise Ratio (SNR) and gains in contrast weighting in several functional and structural acquisitions. Unfortunately, an increase in field strength also induces non-uniformities in the transmit field (B1+) that can compromise image contrast non-uniformly. The MPRAGE is one of the most common T1 weighted (T1w) image acquisitions for structural imaging. It provides excellent contrast between gray and white matter and is widely used for brain segmentation. At 7T, the signal non-uniformities tend to complicate this and therefore, the self-bias-field corrected MP2RAGE is often used there. In both MPRAGE and MP2RAGE, more homogeneous image contrast can be achieved with adiabatic pulses, like the TR-FOCI inversion pulse, or special pulse design on parallel transmission systems, like Universal Pulses (UP). In the present study, we investigate different strategies to improve the bias-field for MPRAGE at 7T, comparing the contrast and GM/WM segmentability against MP2RAGE. The higher temporal efficiency of MPRAGE combined with the potential of the user-friendly UPs was the primary motivation for this MPRAGE-MP2RAGE comparison. We acquired MPRAGE data in six volunteers, adding a k-space shutter to reduce scan time, a kt-point UP approach for homogeneous signal excitation, and a TR-FOCI pulse for homogeneous inversion. Our results show remarkable signal contrast improvement throughout the brain, including regions of low B1 + such as the cerebellum. The improvements in the MPRAGE were largest following the introduction of the UPs. In addition to the CNR, both SNR and GM/WM segmentability were also assessed. Among the MPRAGEs, the combined strategy (UP + TR-FOCI) yielded highest SNR and showed highest spatial similarity between GM segments to the MP2RAGE. Interestingly, the distance between gray and white matter peaks in the intensity histograms did not increase, as better pulses and higher SNR especially benefitted the (cerebellar) gray matter. Overall, the gray-white matter contrast from MP2RAGE is higher, with higher CNR and higher intensity peak distances, even when scaled to scan time. Hence, the extra acquisition time for MP2RAGE is justified by the improved segmentability., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

White matter deterioration is associated with cognitive impairment in healthy aging and Alzheimer's disease. It is critical to identify interventions that can slow down white matter deterioration. So far, clinical trials have failed to demonstrate the benefits of aerobic exercise on the adult white matter using diffusion Magnetic Resonance Imaging. Here, we report the effects of a 6-month aerobic walking and dance interventions (clinical trial NCT01472744) on white matter integrity in healthy older adults (n = 180, 60-79 years) measured by changes in the ratio of calibrated T1- to T2-weighted images (T1w/T2w). Specifically, the aerobic walking and social dance interventions resulted in positive changes in the T1w/T2w signal in late-myelinating regions, as compared to widespread decreases in the T1w/T2w signal in the active control. Notably, in the aerobic walking group, positive change in the T1w/T2w signal correlated with improved episodic memory performance. Lastly, intervention-induced increases in cardiorespiratory fitness did not correlate with change in the T1w/T2w signal. Together, our findings suggest that white matter regions that are vulnerable to aging retain some degree of plasticity that can be induced by aerobic exercise training. In addition, we provided evidence that the T1w/T2w signal may be a useful and broadly accessible measure for studying short-term within-person plasticity and deterioration in the adult human white matter., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Brain activation mapping using functional magnetic resonance imaging (fMRI) has been extensively studied in brain gray matter (GM), whereas in large disregarded for probing white matter (WM). This unbalanced treatment has been in part due to controversies in relation to the nature of the blood oxygenation level-dependent (BOLD) contrast in WM and its detectability. However, an accumulating body of studies has provided solid evidence of the functional significance of the BOLD signal in WM and has revealed that it exhibits anisotropic spatio-temporal correlations and structure-specific fluctuations concomitant with those of the cortical BOLD signal. In this work, we present an anisotropic spatial filtering scheme for smoothing fMRI data in WM that accounts for known spatial constraints on the BOLD signal in WM. In particular, the spatial correlation structure of the BOLD signal in WM is highly anisotropic and closely linked to local axonal structure in terms of shape and orientation, suggesting that isotropic Gaussian filters conventionally used for smoothing fMRI data are inadequate for denoising the BOLD signal in WM. The fundamental element in the proposed method is a graph-based description of WM that encodes the underlying anisotropy observed across WM, derived from diffusion-weighted MRI data. Based on this representation, and leveraging graph signal processing principles, we design subject-specific spatial filters that adapt to a subject's unique WM structure at each position in the WM that they are applied at. We use the proposed filters to spatially smooth fMRI data in WM, as an alternative to the conventional practice of using isotropic Gaussian filters. We test the proposed filtering approach on two sets of simulated phantoms, showcasing its greater sensitivity and specificity for the detection of slender anisotropic activations, compared to that achieved with isotropic Gaussian filters. We also present WM activation mapping results on the Human Connectome Project's 100-unrelated subject dataset, across seven functional tasks, showing that the proposed method enables the detection of streamline-like activations within axonal bundles., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests in regards to the subject matter discussed in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cognitive trajectories vary greatly across older individuals, and the neural mechanisms underlying these differences remain poorly understood. Here, we investigate the cognitive variability in older adults by linking the influence of white matter microstructure on the task-related organization of fast and effective communications between brain regions. Using diffusion tensor imaging and electroencephalography, we show that individual differences in white matter network organization are associated with network clustering and efficiency in the alpha and high-gamma bands, and that functional network dynamics partly explain individual differences in cognitive control performance in older adults. We show that older individuals with high versus low structural network clustering differ in task-related network dynamics and cognitive performance. These findings were corroborated by investigating magnetoencephalography networks in an independent dataset. This multimodal (fMRI and biological markers) brain connectivity framework of individual differences provides a holistic account of how differences in white matter microstructure underlie age-related variability in dynamic network organization and cognitive performance., (Copyright © 2021. Published by Elsevier Inc.)

Unilateral damage to the frontoparietal network typically impairs saccade target selection within the contralesional visual hemifield. Severity of deficits and the degree of recovery have been associated with widespread network dysfunction, yet it is not clear how these behavioural and functional brain changes relate with the underlying structural white matter tracts. Here, we investigated whether recovery after unilateral prefrontal cortex (PFC) lesions was associated with changes in white matter microstructure across large-scale frontoparietal cortical and thalamocortical networks. Diffusion-weighted imaging was acquired in four male rhesus macaques at pre-lesion, week 1, and week 8-16 post-lesion when target selection deficits largely recovered. Probabilistic tractography was used to reconstruct cortical frontoparietal fiber tracts, including the superior longitudinal fasciculus (SLF) and transcallosal fibers connecting the PFC or posterior parietal cortex (PPC), as well as thalamocortical fiber tracts connecting the PFC and PPC to thalamic nuclei. We found that the two animals with small PFC lesions showed increased fractional anisotropy in both cortical and thalamocortical fiber tracts when behaviour had recovered. However, we found that fractional anisotropy decreased in cortical frontoparietal tracts after larger PFC lesions yet increased in some thalamocortical tracts at the time of behavioural recovery. These findings indicate that behavioural recovery after small PFC lesions may be supported by both cortical and subcortical areas, whereas larger PFC lesions may have induced widespread structural damage and hindered compensatory remodeling in the cortical frontoparietal network., Competing Interests: Declarations of Competing Interest The authors declare no competing financial or non-financial interests., (Copyright © 2021. Published by Elsevier Inc.)

Hearing loss is a heterogeneous disorder thought to affect brain reorganization across the lifespan. Here, structural alterations of the brain due to hearing loss are assessed by using unique effect size metrics based on Cohen's d and Hedges' g. These metrics are used to map coordinates of gray matter (GM) and white matter (WM) alterations from bilateral congenital and acquired hearing loss populations. A systematic review and meta-analysis revealed m = 72 studies with structural alterations measured with magnetic resonance imaging (MRI) (bilateral = 64, unilateral = 8). The bilateral studies categorized hearing loss into congenital and acquired cases (n = 7,445) and control cases (n = 2,924), containing 66,545 datapoint metrics. Hearing loss was found to affect GM and underlying WM in nearly every region of the brain. In congenital hearing loss, GM decreased most in the frontal lobe. Similarly, acquired hearing loss had a decrease in frontal lobe GM, albeit the insula was most decreased. In congenital, WM underlying the frontal lobe GM was most decreased. In congenital, the right hemisphere was more negatively impacted than the left hemisphere; however, in acquired, this was the opposite. The WM alterations most frequently underlined GM alterations in congenital hearing loss, while acquired hearing loss studies did not frequently assess the WM metric. Future studies should use the endophenotype of hearing loss as a prognostic template for discerning clinical outcomes., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests and no non-financial competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Language is the most commonly described lateralised cognitive function, relying more on the left hemisphere compared to the right hemisphere in over 90% of the population. Most research examining the structure-function relationship of language lateralisation only included people showing a left language hemisphere dominance. In this work, we applied a state-of-the-art "fixel-based" analysis approach, allowing statistical analysis of white matter micro- and macrostructure on a fibre-specific level in a sample of participants with left and right language dominance (LLD and RLD). Both groups showed a similar extensive pattern of white matter lateralisation including a comparable leftwards lateralisation of the arcuate fasciculus, regardless of their functional language lateralisation. These results suggest that lateralisation of language functioning and the arcuate fasciculus are driven by independent biases. Finally, a significant group difference of lateralisation was detected in the forceps minor, with a leftwards lateralisation in LLD and rightwards lateralisation for the RLD group., (Copyright © 2021. Published by Elsevier Inc.)

The mismatch negativity (MMN) is an event related brain potential (ERP) elicited by unpredicted sounds presented in a sequence of repeated auditory stimuli. The neural sources of the MMN have been previously attributed to a fronto-temporo-parietal network which crucially overlaps with the so-called auditory dorsal stream, involving inferior and middle frontal, inferior parietal, and superior and middle temporal regions. These cortical areas are structurally connected by the arcuate fasciculus (AF), a three-branch pathway supporting the feedback-feedforward loop involved in auditory-motor integration, auditory working memory, storage of acoustic templates, as well as comparison and update of those templates. Here, we characterized the individual differences in the white-matter macrostructural properties of the AF and explored their link to the electrophysiological marker of passive change detection gathered in a melodic multifeature MMN-EEG paradigm in 26 healthy young adults without musical training. Our results show that left fronto-temporal white-matter connectivity plays an important role in the pre-attentive detection of rhythm modulations within a melody. Previous studies have shown that this AF segment is also critical for language processing and learning. This strong coupling between structure and function in auditory change detection might be related to life-time linguistic (and possibly musical) exposure and experiences, as well as to timing processing specialization of the left auditory cortex. To the best of our knowledge, this is the first time in which the relationship between neurophysiological (EEG) and brain white-matter connectivity indexes using DTI-tractography are studied together. Thus, the present results, although still exploratory, add to the existing evidence on the importance of studying the constraints imposed on cognitive functions by the underlying structural connectivity., (Copyright © 2021. Published by Elsevier Inc.)

Reading-related responses in the lateral ventral temporal cortex (VTC) show a consistent spatial layout across individuals, which is puzzling, since reading skills are acquired during childhood. Here, we tested the hypothesis that white matter fascicles and gray matter microstructure predict the location of reading-related responses in lateral VTC. We obtained functional (fMRI), diffusion (dMRI), and quantitative (qMRI) magnetic resonance imaging data in 30 adults. fMRI was used to map reading-related responses by contrasting responses in a reading task with those in adding and color tasks; dMRI was used to identify the brain's fascicles and to map their endpoint densities in lateral VTC; qMRI was used to measure proton relaxation time (T 1 ), which depends on cortical tissue microstructure. We fit linear models that predict reading-related responses in lateral VTC from endpoint density and T 1 and used leave-one-subject-out cross-validation to assess prediction accuracy. Using a subset of our participants (N=10, feature selection set), we find that i) endpoint densities of the arcuate fasciculus (AF), inferior longitudinal fasciculus (ILF), and vertical occipital fasciculus (VOF) are significant predictors of reading-related responses, and ii) cortical T 1 of lateral VTC further improves the predictions of the fascicle model. In the remaining participants (N=20, validation set), we show that a linear model that includes T 1 , AF, ILF and VOF significantly predicts i) the map of reading-related responses across lateral VTC and ii) the location of the visual word form area, a region critical for reading. Overall, our data-driven approach reveals that the AF, ILF, VOF and cortical microstructure have a consistent spatial relationship with an individual's reading-related responses in lateral VTC., Competing Interests: Declaration of Competing Interests The authors declare no competing interests., (Copyright © 2020. Published by Elsevier Inc.)

The corpus callosum serves as a crucial organization for understanding the information integration between the two hemispheres. Our previous study explored the functional connectivity between the corpus callosum and white-matter functional networks (WM-FNs), but the corresponding physical connectivity remains unknown. The current study uses the resting-state fMRI of Human Connectome Project data to identify ten WM-FNs in 108 healthy subjects, and then independently maps the structural and functional connectivity between the corpus callosum and above WM-FNs using the diffusion tensor images (DTI) tractography and resting-state functional connectivity (RSFC). Our results demonstrated that the structural and functional connectivity between the human corpus callosum and WM-FNs have the following high overall correspondence: orbitofrontal WM-FN, DTI map = 89% and RSFC map = 92%; sensorimotor middle WM-FN, DTI map = 47% and RSFC map = 77%; deep WM-FN, DTI map = 50% and RSFC map = 79%; posterior corona radiata WM-FN, DTI map = 82% and RSFC map = 73%. These findings reinforce the notion that the corpus callosum has unique spatial distribution patterns connecting to distinct WM-FNs. However, important differences between the structural and functional connectivity mapping results were also observed, which demonstrated a synergy between DTI tractography and RSFC toward better understanding the information integration of primary and higher-order functional systems in the human brain., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Understanding the development of white matter microstructure in the general population is an imperative precursor to identifying its involvement in psychopathology. Previous studies have reported changes in white matter microstructure associated with age and different developmental patterns between boys and girls. Handedness has also been related to white matter in adults. Motor performance, tightly dependent on overall neuronal myelination, has been related to the corpus callosum. However, the association between motor performance and global white matter microstructure has not been reported in the literature. In general, these age, sex, handedness, and motor performance associations have been observed using small and poorly representative samples. We examined the relationships between age, sex, handedness, and motor performance, measured with a finger tapping task, and white matter microstructure in the forceps major and minor and in 5 tracts bilaterally (cingulum, corticospinal, inferior and superior longitudinal fasciculi, and uncinate) in a population-based sample of 3031 children between 8 and 12 years of age. Diffusion tensor imaging (DTI) data were acquired using a single, study-dedicated 3 Tesla scanner. We extracted and quantified features of white matter microstructure for each tract. We computed global DTI metrics by combining scalar values across multiple tracts into single latent factors using a confirmatory factor analysis. The adjusted linear regression models indicated that age was associated with global fractional anisotropy (FA), global mean diffusivity (MD), and almost all the tracts. Further, girls showed lower global MD than boys, while FA values differed by tract, and no age-sex interactions were found. No differences were observed in white matter microstructure between right- and left-handed children. We observed that FA in forceps major was associated with right-hand finger tapping performance. White matter FA in association tracts was only related to motor function before multiple testing correction. Our findings do not provide evidence for a relationship between finger tapping task performance and global white matter microstructure., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Inc.)

The ability to recognize the structural components of words, known as morphological processing, was recently associated with the bilateral ventral white matter pathways, across different writing systems. However, it remains unclear whether these associations are specific to the context of reading. To shed light on this question, in the current study we investigated whether the ventral pathways are associated with morphological processing in an oral word production task that does not involve reading. Forty-five participants completed a morpheme-based fluency task in Hebrew, as well as diffusion MRI (dMRI) scans. We used probabilistic tractography to segment the major ventral and dorsal white matter pathways, and assessed the correlations between their microstructural properties and performance on the morpheme-based fluency task. We found significant correlations between morpheme-based fluency and properties of the bilateral ventral tracts, suggesting that the involvement of these tracts in morphological processing extends beyond the reading modality. In addition, significant correlations were found in the frontal aslant tract (FAT), a dorsal tract associated with oral fluency and speech production. Together, our findings emphasize that neurocognitive associations reflect both the cognitive construct under investigation as well as the task used for its assessment. Lastly, to elucidate the biological factors underlying these correlations, we incorporated the composite hindered and restricted model of diffusion (CHARMED) framework, measured in independent scans. We found that only some of our findings could be attributed to variation in a CHARMED-based estimate of fiber density. Further, we were able to uncover additional correlations that could not be detected using traditional dMRI indices. In sum, our results show that the involvement of the ventral tracts in morphological processing extends to the production domain, and demonstrate the added value of including sensitive structural measurements in neurocognitive investigations., (Copyright © 2020. Published by Elsevier Inc.)

We aimed to link macro- and microstructure measures of brain white matter obtained from diffusion MRI with effective connectivity measures based on a propagation of cortico-cortical evoked potentials induced with intrasurgical direct electrical stimulation. For this, we compared streamline lengths and log-transformed ratios of streamlines computed from presurgical diffusion-weighted images, and the delays and amplitudes of N1 peaks recorded intrasurgically with electrocorticography electrodes in a pilot study of 9 brain tumor patients. Our results showed positive correlation between these two modalities in the vicinity of the stimulation sites (Pearson coefficient 0.54±0.13 for N1 delays, and 0.47±0.23 for N1 amplitudes), which could correspond to the neural propagation via U-fibers. In addition, we reached high sensitivities (0.78±0.07) and very high specificities (0.93±0.03) in a binary variant of our comparison. Finally, we used the structural connectivity measures to predict the effective connectivity using a multiple linear regression model, and showed a significant role of brain microstructure-related indices in this relation., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Networks in the prefrontal cortex (PFC) that are important for executive function are also engaged in adaptive responding to negative events. These networks are particularly vulnerable to age-related structural atrophy and an associated loss of executive function, yet existing evidence suggests preserved emotion processing ability in ageing. Using longitudinally acquired data from a battery of cognitive tasks, we defined a metric for the rate of decline of executive function. With this metric, we investigated relationships between changes in executive function and emotion reappraisal ability and brain structure, in 34 older adults, using functional and structural MRI. During task-based fMRI, participants were asked to cognitively reappraise negatively valenced images. We hypothesised one of two associations with decreasing executive function over time: 1) a decreased ability to reappraise reflected in decreased PFC and increased amygdala activation, or 2) a neural compensation mechanism characterised by increased PFC activation but no differential amygdala activation. Structurally, for a decreased reappraisal ability, we predicted a decrease in grey matter in PFC and/or a decrease of white matter integrity in amygdala-PFC pathways. Neither of the two hypotheses relating to brain function were completely supported, with the findings indicating a steeper decline in executive function associated with both increased PFC and increased left amygdala activity when reappraising negative stimuli. In addition, white matter integrity of the uncinate fasciculus, a primary white matter tract connecting the amygdala and ventromedial areas of PFC, was lower in those individuals who demonstrated a greater decrease in executive function. These findings highlight the association of diminishing cognitive ability with brain structure and function linked to emotion regulation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Inc.)

Recently, it has been proposed that the harmonic patterns emerging from the brain's structural connectivity underlie the resting state networks of the human brain. These harmonic patterns, termed connectome harmonics, are estimated as the Laplace eigenfunctions of the combined gray and white matters connectivity matrices and yield a connectome-specific extension of the well-known Fourier basis. However, it remains unclear how topological properties of the combined connectomes constrain the precise shape of the connectome harmonics and their relationships to the resting state networks. Here, we systematically study how alterations of the local and long-range connectivity matrices affect the spatial patterns of connectome harmonics. Specifically, the proportion of local gray matter homogeneous connectivity versus long-range white-matter heterogeneous connectivity is varied by means of weight-based matrix thresholding, distance-based matrix trimming, and several types of matrix randomizations. We demonstrate that the proportion of local gray matter connections plays a crucial role for the emergence of wide-spread, functionally meaningful, and originally published connectome harmonic patterns. This finding is robust for several different cortical surface templates, mesh resolutions, or widths of the local diffusion kernel. Finally, using the connectome harmonic framework, we also provide a proof-of-concept for how targeted structural changes such as the atrophy of inter-hemispheric callosal fibers and gray matter alterations may predict functional deficits associated with neurodegenerative conditions., (Copyright © 2020. Published by Elsevier Inc.)

Most magnetic resonance imaging (MRI) studies investigating the relationship between regional brain myelination or axonal density and aging have relied upon nonspecific methods to probe myelin and axonal content, including diffusion tensor imaging and relaxation time mapping. While these studies have provided pivotal insights into changes in cerebral architecture with aging and pathology, details of the underlying microstructural alterations have not been fully elucidated. In the current study, we used the BMC-mcDESPOT analysis, a direct and specific multicomponent relaxometry method for imaging of myelin water fraction (MWF), a marker of myelin content, and NODDI, an emerging multicomponent diffusion technique, for neurite density index (NDI) imaging, a proxy of axonal density. We investigated age-related differences in MWF and NDI in several white matter brain regions in a cohort of cognitively unimpaired participants over a wide age range. Our results indicate a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by a decrease at older ages, in agreement with previous work. We found a similarly complex regional association between NDI and age, with several cerebral structures also exhibiting a quadratic, inverted U-shape, relationship. This novel observation suggests an increase in axonal density until the fourth decade of age followed by a rapid loss at older ages. We also observed that these age-related differences in MWF and NDI vary across different brain regions, as expected. Finally, our study indicates no significant association between MWF and NDI in most cerebral structures investigated, although this association approached significance in a limited number of brain regions, indicating the complementary nature of their information and encouraging further investigation. Overall, we find evidence of nonlinear associations between age and myelin or axonal density in a sample of well-characterized adults, using direct myelin and axonal content imaging methods., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020. Published by Elsevier Inc.)

Spontaneous fluctuations in MRI signals from gray matter (GM) in the brain are interpreted as originating from variations in neural activity, and their inter-regional correlations may be analyzed to reveal functional connectivity. However, most studies of intrinsic neuronal activity have ignored the spontaneous fluctuations that also arise in white matter (WM). In this work, we explore spontaneous fluctuations in resting state MRI signals in WM based on spatial independent component analyses (ICA), a data-driven approach that separates signals into independent sources without making specific modeling assumptions. ICA has become widely accepted as a valuable approach for identifying functional connectivity within cortex but has been rarely applied to derive equivalent structures within WM. Here, BOLD signal changes in WM of a group of subjects performing motor tasks were first detected using ICA, and a spatial component whose time course was consistent with the task was found, demonstrating the analysis is sensitive to evoked BOLD signals in WM. Secondly, multiple spatial components were derived by applying ICA to identify those voxels in WM whose MRI signals showed similar temporal behaviors in a resting state. These functionally-related structures are grossly symmetric and coincide with corresponding tracts identified from diffusion MRI. Finally, functional connectivity was quantified by calculating correlations between pairs of structures to explore the synchronicity of resting state BOLD signals across WM regions, and the experimental results revealed that there exist two distinct groupings of functional correlations in WM tracts at rest. Our study provides further insights into the nature of activation patterns, functional responses and connectivity in WM, and support previous suggestions that BOLD signals in WM show similarities with cortical activations and are characterized by distinct underlying structures in tasks and at rest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Brain age is becoming a widely applied imaging-based biomarker of neural aging and potential proxy for brain integrity and health. We estimated multimodal and modality-specific brain age in the Whitehall II (WHII) MRI cohort using machine learning and imaging-derived measures of gray matter (GM) morphology, white matter microstructure (WM), and resting state functional connectivity (FC). The results showed that the prediction accuracy improved when multiple imaging modalities were included in the model (R 2 = 0.30, 95% CI [0.24, 0.36]). The modality-specific GM and WM models showed similar performance (R 2 = 0.22 [0.16, 0.27] and R 2 = 0.24 [0.18, 0.30], respectively), while the FC model showed the lowest prediction accuracy (R 2 = 0.002 [-0.005, 0.008]), indicating that the FC features were less related to chronological age compared to structural measures. Follow-up analyses showed that FC predictions were similarly low in a matched sub-sample from UK Biobank, and although FC predictions were consistently lower than GM predictions, the accuracy improved with increasing sample size and age range. Cardiovascular risk factors, including high blood pressure, alcohol intake, and stroke risk score, were each associated with brain aging in the WHII cohort. Blood pressure showed a stronger association with white matter compared to gray matter, while no differences in the associations of alcohol intake and stroke risk with these modalities were observed. In conclusion, machine-learning based brain age prediction can reduce the dimensionality of neuroimaging data to provide meaningful biomarkers of individual brain aging. However, model performance depends on study-specific characteristics including sample size and age range, which may cause discrepancies in findings across studies., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The ability to effectively suppress motor response tendencies is essential for focused and goal-directed behavior. Here, we tested the hypothesis that developmental improvement in the ability to cancel a motor response is reflected by maturational changes in the white matter underlying the right presupplementary motor area (preSMA) and posterior inferior frontal gyrus (IFG), two cortical key areas of the fronto-basal ganglia "stopping" network. Eighty-eight typically-developing children and adolescents, aged 7-19 years, were longitudinally assessed with the stop-signal task (SST) and diffusion tensor imaging (DTI) of the brain over a period of six years. Participants were examined from two to nine times with an average of 6.6 times, resulting in 576 SST-DTI datasets. We applied tract-based spatial statistics to extract mean fractional anisotropy (FA) from regions-of-interest in the white matter underlying the right IFG (IFG FA ) and right preSMA (preSMA FA ) at each time point. Motor response cancelation performance, estimated with the stop-signal reaction time (SSRT), improved with age. Initially well performing children plateaued around the age of 11 years, while initially poor performers caught up at the age of 13-14 years. White matter microstructure continued to mature across the investigated age range. Males generally displayed linear maturational trajectories, while females displayed more curvilinear trajectories that leveled off around 12-14 years of age. Maturational increases in right preSMA FA but not right IFG FA were associated with developmental improvements in SSRT. This association differed depending on the mean right preSMA FA across the individual maturational trajectory. Children with lower mean right preSMA FA exhibited poorer SSRT performance at younger ages but steeper developmental trajectories of SSRT improvement. Children with higher mean right preSMA FA exhibited flatter trajectories of SSRT improvement along with faster SSRT already at the first assessments. The results suggest that no further improvement in motor response cancellation is achieved once a certain level of maturity in the white matter underlying the right preSMA is reached. Similar dynamics may apply to other behavioral read-outs and brain structures and, thus, need to be considered in longitudinal MRI studies designed to map brain structural correlates of behavioral changes during development., Competing Interests: Declaration of competing interest Hartwig R. Siebner has received honoraria as speaker and ad-hoc consultant from Sanofi Genzyme, Denmark and Novartis, Denmark and as editor-in-chief (NeuroImage Clinical) and senior editor (NeuroImage) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as book editor from Springer Publishers, Stuttgart, Germany. The authors declare no potential conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Determining the anatomical source of brain activity non-invasively measured from EEG or MEG sensors is challenging. In order to simplify the source localization problem, many techniques introduce the assumption that current sources lie on the cortical surface. Another common assumption is that this current flow is orthogonal to the cortical surface, thereby approximating the orientation of cortical columns. However, it is not clear which cortical surface to use to define the current source locations, and normal vectors computed from a single cortical surface may not be the best approximation to the orientation of cortical columns. We compared three different surface location priors and five different approaches for estimating dipole vector orientation, both in simulations and visual and motor evoked MEG responses. We show that models with source locations on the white matter surface and using methods based on establishing correspondences between white matter and pial cortical surfaces dramatically outperform models with source locations on the pial or combined pial/white surfaces and which use methods based on the geometry of a single cortical surface in fitting evoked visual and motor responses. These methods can be easily implemented and adopted in most M/EEG analysis pipelines, with the potential to significantly improve source localization of evoked responses., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Declining auditory spatial processing is hypothesized to contribute to the difficulty older adults have detecting, locating, and selecting a talker from among others in noisy listening environments. Though auditory spatial processing has been associated with several cortical structures, little is known regarding the underlying white matter architecture or how age-related changes in white matter microstructure may affect it. The arcuate fasciculus is a target for understanding age-related differences in auditory spatial attention based on normative spatial attention findings in humans. Similarly, animal and human clinical studies suggest that the corpus callosum plays a role in the cross-hemispheric integration of auditory spatial information important for spatial localization and attention. The current investigation used diffusion imaging to examine the extent to which age-group differences in the identification of spatially cued speech were accounted for by individual differences in the white matter microstructure of the right arcuate fasciculus and the corpus callosum. Higher right arcuate and callosal fractional anisotropy (FA) predicted better segregation and identification of spatially cued speech across younger and older listeners. Further, individual differences in callosal microstructure mediated age-group differences in auditory spatial processing. Follow-up analyses suggested that callosal tracts connecting left and right pre-frontal and posterior parietal cortex are particularly important for auditory spatial processing. The results are consistent with previous work in animals and clinical human samples and provide a cortical mechanism to account for age-related deficits in auditory spatial processing. Further, the results suggest that both intrahemispheric and interhemispheric mechanisms are involved in auditory spatial processing., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study examined within-subject differences among three fluid abilities that decline with age: reasoning, episodic memory and processing speed, compared with vocabulary, a crystallized ability that is maintained with age. The data were obtained from the Reference Ability Neural Network (RANN) study from which 221 participants had complete behavioral data for all 12 cognitive tasks, three per ability, along with fMRI and diffusion weighted imaging data. We used fMRI task activation to guide white matter tractography, and generated mean percent signal change in the regions associated with the processing of each ability along with diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), for each cognitive ability. Qualitatively brain regions associated with vocabulary were more localized and lateralized to the left hemisphere whereas the fluid abilities were associated with brain activations that were more distributed across the brain and bilaterally situated. Using continuous age, we observed smaller correlations between MD and age for white matter tracts connecting brain regions associated with the vocabulary ability than that for the fluid abilities, suggesting that vocabulary white matter tracts were better maintained with age. Furthermore, after multiple comparisons correction and accounting for age, education, and sex, the mean percent signal change for episodic memory showed positive associations with behavioral performance. Overall, the vocabulary ability may be better maintained with age due to the more localized brain regions involved, which places smaller reliance on long distance white matter tracts for signal transduction. These results support the hypothesis that functional activation and white matter structures underlying the vocabulary ability contribute to the ability's greater resistance against aging., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Measuring fibre dispersion in white matter with diffusion magnetic resonance imaging (MRI) is limited by an inherent degeneracy between fibre dispersion and microscopic diffusion anisotropy (i.e., the diffusion anisotropy expected for a single fibre orientation). This means that estimates of fibre dispersion rely on strong assumptions, such as constant microscopic anisotropy throughout the white matter or specific biophysical models. Here we present a simple approach for resolving this degeneracy using measurements that combine linear (conventional) and spherical tensor diffusion encoding. To test the accuracy of the fibre dispersion when our microstructural model is only an approximation of the true tissue structure, we simulate multi-compartment data and fit this with a single-compartment model. For such overly simplistic tissue assumptions, we show that the bias in fibre dispersion is greatly reduced (~5x) for single-shell linear and spherical tensor encoding data compared with single-shell or multi-shell conventional data. In in-vivo data we find a consistent estimate of fibre dispersion as we reduce the b-value from 3 to 1.5 ms/μm 2 , increase the repetition time, increase the echo time, or increase the diffusion time. We conclude that the addition of spherical tensor encoded data to conventional linear tensor encoding data greatly reduces the sensitivity of the estimated fibre dispersion to the model assumptions of the tissue microstructure., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Understanding how the anatomy of the human brain constrains and influences the formation of large-scale functional networks remains a fundamental question in neuroscience. Here, given measured brain activity in gray matter, we interpolate these functional signals into the white matter on a structurally-informed high-resolution voxel-level brain grid. The interpolated volumes reflect the underlying anatomical information, revealing white matter structures that mediate the interaction between temporally coherent gray matter regions. Functional connectivity analyses of the interpolated volumes reveal an enriched picture of the default mode network (DMN) and its subcomponents, including the different white matter bundles that are implicated in their formation, thus extending currently known spatial patterns that are limited within the gray matter only. These subcomponents have distinct structure-function patterns, each of which are differentially observed during tasks, demonstrating plausible structural mechanisms for functional switching between task-positive and -negative components. This work opens new avenues for the integration of brain structure and function, and demonstrates the collective mediation of white matter pathways across short and long-distance functional connections., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The mapping of human brain connections is still an on going task. Unlike deep white matter (DWM), which has been extensively studied and well documented, superficial white matter (SWM) has been often left aside. Improving our understanding of the SWM is an important goal for a better understanding of the brain network and its relation to several pathologies. The shape and localization of these short bundles present a high variability across subjects. Furthermore, the small diameter of most superficial bundles and partial volume effects induced by their proximity to the cortex leads to complex tratography issues. Therefore, the mapping of SWM bundles and the use of the resulting atlases for clinical studies requiere dedicated methodologies that are reviewed in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Fluid intelligence (Gf) is the innate ability of an individual to respond to complex and unexpected situations. Although some studies have considered that the multiple-demand (MD) system of the brain was the biological foundation for Gf, further characterization of their relationships in the context of aging is limited. The present study hypothesized that the structural metrics of the MD system, including cortical thickness, cortical volumes, and white matter (WM) tract integrity, was the brain correlates for Gf across the adult life span. Partial correlation analysis was performed to investigate whether the MD system could still explain Gf independent of the age effect. Moreover, the partial correlations between Gf and left/right structural metrics within the MD regions were compared to test whether the correlations displayed distinct lateralization., Methods: The participants were recruited from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) databank, comprising the images of 603 healthy participants aged 18-88 years acquired on a 3-T system. The MRI data included high-resolution T1-weighted and diffusion-weighted images, from which gray matter and WM structural metrics of the MD system were analyzed, respectively. The structural metrics of gray matter were quantified in terms of cortical volume/thickness of five pairs of cortical regions, and those of WM were quantified in terms of the mean axial diffusivity (D A ), radial diffusivity (D R ), mean diffusivity (D M ), and generalized fractional anisotropy (GFA) on five pairs of tracts. Partial correlation controlling for age and sex effects, was performed to investigate the associations of Gf scores with the mean D A , D R , D M and GFA of all tracts in the MD system, those of left and right hemispheric tracts, and those of each tract. Fisher's exact test was used to compare the partial correlations between left and right MD regions., Results: The linear relationship between cortical volumes and Gf was evident across all levels of the MD system even after controlling for age and sex. For the WM integrity, diffusion indices including D A , D R , D M and GFA displayed linear relationships with Gf scores at various levels of the MD system. Among the 10 WM tracts connecting the MD regions, bilateral superior longitudinal fasciculus I and bilateral frontal aslant tracts exhibited the strongest and significant associations. Our results did not show significant inter-hemispheric differences in the associations between structural metrics of the MD system and Gf., Conclusion: Our results demonstrate significant associations between Gf and both cortical volumes and tract integrity of the MD system across the adult lifespan in a population-based cohort. We found that the association remained significant in the entire adult lifespan despite simultaneous decline of Gf and the MD system. Our results suggest that the MD system might be a structural underpinning of Gf and support the fronto-parietal model of cognitive aging. However, we did not find hemispheric differences in the Gf-MD correlations, not supporting the hemi-aging hypothesis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Displacement Encoding with Stimulated Echoes (DENSE) has recently shown potential for measuring cardiac-induced cerebral volumetric strain in the human brain. As such, it may provide a powerful tool for investigating the cerebral small vessels. However, further development and validation are necessary. This study aims, first, to validate a retrospectively-gated implementation of the DENSE method for assessing brain tissue pulsations as a physiological marker, and second, to use the acquired measurements to explore intracranial volume dynamics. We acquired repeated measurements of cerebral volumetric strain in 8 healthy subjects, and internally validated these measurements by comparing them to spinal CSF stroke volumes obtained in the same scan session. Peak volumetric strain was found to be highly repeatable between scan sessions. First/second measured peak volumetric strains were: (6.4 ​± ​1.7)x10 -4 /(6.7 ​± ​1.6)x10 -4 for whole brain, (9.5 ​± ​2.5)x10 -4 /(9.6 ​± ​2.4)x10 -4 for grey matter, and (4.4 ​± ​1.7)x10 -4 /(4.1 ​± ​0.8)x10 -4 for white matter. Grey matter showed significantly higher peak strain (p ​< ​0.001) and earlier time-to-peak strain (p ​< ​0.02) than white matter. An approximately linear relationship was found between CSF and brain tissue volume pulsations over the cardiac cycle (mean slope and R 2 of 0.88 ​± ​0.23 and 0.89 ​± ​0.07, respectively). The close similarity between CSF and brain tissue volume pulsations implies limited contributions from large intracranial vessel pulsations, providing further evidence for venous compression as an additional mechanism for maintaining stable intracranial pressures over the cardiac cycle. Cerebral pulsatility showed consistent inter-subject peak values in healthy subjects, and was strongly correlated to CSF stroke volumes. These results strengthen the potential of brain tissue volumetric strain as a means for investigating the intracranial dynamics of the ageing brain in normal or diseased states., Competing Interests: Declaration of competing interest The authors have no conflict of interests to disclose., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Children with unilateral resections of ventral occipito-temporal cortex (VOTC) typically do not evince visual perceptual impairments, even when relatively large swathes of VOTC are resected. In search of possible explanations for this behavioral competence, we evaluated white matter microstructure and connectivity in eight pediatric epilepsy patients following unilateral cortical resection and 15 age-matched controls. To uncover both local and broader resection-induced effects, we analyzed tractography data using two complementary approaches. First, the microstructural properties were measured in the inferior longitudinal and the inferior fronto-occipital fasciculi, the major VOTC association tracts. Group differences were only evident in the ipsilesional, and not in the contralesional, hemisphere, and single-subject analyses revealed that these differences were limited to the site of the resection. Second, graph theory was used to characterize the connectivity of the contralesional occipito-temporal regions. There were no changes to the network properties in patients with left VOTC resections nor in patients with resections outside the VOTC, but altered network efficiency was observed in two cases with right VOTC resections. These results suggest that, in many, although perhaps not all, cases of unilateral VOTC resections in childhood, the white matter profile in the preserved contralesional hemisphere along with residual neural activity might be sufficient for normal visual perception., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Brain metabolites, such as N-acetylaspartate or myo-inositol, are constantly probing their local cellular environment under the effect of diffusion. Diffusion-weighted NMR spectroscopy therefore presents unparalleled potential to yield cell-type specific microstructural information. Double diffusion encoding (DDE) consists in applying two diffusion blocks, where gradient's direction in the second block is varied during the course of the experiment. Unlike single diffusion encoding, DDE measurements at long mixing time display some angular modulation of the signal amplitude which reflects microscopic anisotropy (μA), while requiring relatively low gradient strength. This angular dependence has been formerly used to quantify cell fiber diameter using a model of isotropically oriented infinite cylinders. However, how additional features of the cell microstructure (such as cell body diameter, fiber length and branching) may also influence the DDE signal has been little explored. Here, we used a cryoprobe as well as state-of-the-art post-processing to perform DDE acquisitions with high accuracy and precision in the mouse brain at 11.7 ​T. We then compared our results to simulated DDE datasets obtained in various 3D cell models in order to pinpoint which features of cell morphology may influence the most the angular dependence of the DDE signal. While the infinite cylinder model poorly fits our experimental data, we show that incorporating branched fiber structure in our model allows more realistic interpretation of the DDE signal. Lastly, data acquired in the short mixing time regime suggest that some sensitivity to cell body diameter might be retrieved, although additional experiments would be required to further support this statement., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuroimaging has revealed numerous neural predictors of individual differences in creativity; however, with most of these identified in only one study, sometimes involving very small samples, their reliability is uncertain. To contribute to a convergent cognitive neuroscience of creativity, we conducted a pre-registered conceptual replication and extension study in which we assessed previously reported predictors of creativity using a multimodal approach, incorporating volumetric, white matter, and functional connectivity neuroimaging data. We assessed sets of pre-registered predictors against prevailing measures of creativity, including visual and verbal tests of divergent thinking, everyday creative behaviour, and creative achievement. We then conducted whole-brain exploratory analyses. Greater creativity was broadly predicted by features of the inferior frontal gyrus (IFG) and inferior parietal lobe (IPL), including both local grey matter and white matter predictors in the IFG, the superior longitudinal fasciculus that connects them, and IFG-IPL functional connectivity. As IFG and IPL are important nodes within executive control and default mode networks (DMN), respectively, this result supports the view that executive modulation of DMN activity optimizes creative ideation. Furthermore, white matter integrity of the basal ganglia was also a generalizable creativity predictor, and exploratory analyses revealed the anterior lobe of the cerebellum and the parahippocampal gyrus to both be reliable predictors of creativity across neuroimaging modalities. This pattern aligns with proposals ascribing roles of working and long-term memory to problem-solving and imagination. Overall, our findings help to consolidate some, but not all, neural correlates of individual differences that have been discussed in the cognitive neuroimaging of creativity, yielding a subset that appear particularly promising for focused future investigation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The structural and functional organization of brain networks subserving basic daily activities (i.e. language, visuo-spatial cognition, movement, semantics, etc.) are not completely understood to date. Here, we report the first probabilistic cortical and subcortical atlas of critical structures mediating human brain functions based on direct electrical stimulation (DES), a well-validated tool for the exploration of cerebral processing and for performing safe surgical interventions in eloquent areas., Methods: We collected 1162 cortical and 659 subcortical DES responses during testing of 16 functional domains in 256 patients undergoing awake surgery. Spatial coordinates for each functional response were calculated, and probability distributions for the entire patient cohort were mapped onto a standardized three-dimensional brain template using a multinomial statistical analysis. In addition, matching analyses were performed against prior established anatomy-based cortical and white matter (WM) atlases., Results: The probabilistic maps for each functional domain were provided. The topographical analysis demonstrated a wide spatial distribution of cortical functional responses, while subcortical responses were more restricted, localizing to known WM pathways. These DES-derived data showed reliable matching with existing cortical and WM atlases as well as recent neuroimaging and neurophysiological data., Conclusions: We present the first integrated and comprehensive cortical-subcortical atlas of structures essential for humans' neural functions based on highly-specific DES mapping during real-time neuropsychological testing. This novel atlas can serve as a complementary tool for neuroscientists, along with data obtained from other modalities, to improve and refine our understanding of the functional anatomy of critical brain networks., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Transcranial magnetic stimulation (TMS) is often targeted using a model of TMS-induced electric field (E). In such navigated TMS, the E-field models have been based on spherical approximation of the head. Such models omit the effects of cerebrospinal fluid (CSF) and gyral folding, leading to potentially large errors in the computed E-field. So far, realistic models have been too slow for interactive TMS navigation. We present computational methods that enable real-time solving of the E-field in a realistic five-compartment (5-C) head model that contains isotropic white matter, gray matter, CSF, skull and scalp. Using reciprocity and Geselowitz integral equation, we separate the computations to coil-dependent and -independent parts. For the Geselowitz integrals, we present a fast numerical quadrature. Further, we present a moment-matching approach for optimizing dipole-based coil models. We verified and benchmarked the new methods using simulations with over 100 coil locations. The new quadrature introduced a relative error (RE) of 0.3-0.6%. For a coil model with 42 dipoles, the total RE of the quadrature and coil model was 0.44-0.72%. Taking also other model errors into account, the contribution of the new approximations to the RE was 0.1%. For comparison, the RE due to omitting the separation of white and gray matter was >11%, and the RE due to omitting also the CSF was >23%. After the coil-independent part of the model has been built, E-fields can be computed very quickly: Using a standard PC and basic GPU, our solver computed the full E-field in a 5-C model in 9000 points on the cortex in 27 coil positions per second (cps). When the separation of white and gray matter was omitted, the speed was 43-65 cps. Solving only one component of the E-field tripled the speed. The presented methods enable real-time solving of the TMS-induced E-field in a realistic head model that contains the CSF and gyral folding. The new methodology allows more accurate targeting and precise adjustment of stimulation intensity during experimental or clinical TMS mapping., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The human brain can be described as a network of specialized and spatially distributed regions. The activity of individual regions can be estimated using electroencephalography and the structure of the network can be measured using diffusion magnetic resonance imaging. However, the communication between the different cortical regions occurring through the white matter, coined information flow, cannot be observed by either modalities independently. Here, we present a new method to infer information flow in the white matter of the brain from joint diffusion MRI and EEG measurements. This is made possible by the millisecond resolution of EEG which makes the transfer of information from one region to another observable. A subject specific Bayesian network is built which captures the possible interactions between brain regions at different times. This network encodes the connections between brain regions detected using diffusion MRI tractography derived white matter bundles and their associated delays. By injecting the EEG measurements as evidence into this model, we are able to estimate the directed dynamical functional connectivity whose delays are supported by the diffusion MRI derived structural connectivity. We present our results in the form of information flow diagrams that trace transient communication between cortical regions over a functional data window. The performance of our algorithm under different noise levels is assessed using receiver operating characteristic curves on simulated data. In addition, using the well-characterized visual motor network as grounds to test our model, we present the information flow obtained during a reaching task following left or right visual stimuli. These promising results present the transfer of information from the eyes to the primary motor cortex. The information flow obtained using our technique can also be projected back to the anatomy and animated to produce videos of the information path through the white matter, opening a new window into multi-modal dynamic brain connectivity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Task based and resting state fMRI has been widely utilized to study brain functions. As the foundation of fMRI, the underlying neural basis of the BOLD signal has been extensively studied, but the detailed mechanism remains elusive, particularly during the resting state. To examine the neurovascular coupling, it is important to simultaneously record neural and vascular signals. Here we developed a novel setup of camera based, scalable simultaneous calcium fiber photometry and fMRI in rats. Using this setup, we recorded calcium signals of superior colliculus (SC) and lateral geniculate nucleus (LGN) and fMRI simultaneously during visual stimulation and the resting state. Our results revealed robust, region-specific coupling between calcium and BOLD signals in the task state and weaker, whole brain correlation in the resting state. Interestingly, the spatial specificity of such correlation in the resting state was improved upon regression of white matter, ventricle signals and global signals in fMRI data. Overall, our results suggest differential coupling of calcium and BOLD signals for subcortical regions between evoked and resting states, and the coupling relationship in the resting state was related with resting state BOLD preprocessing strategies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A single nucleotide polymorphism (SNP) in the gene coding for brain-derived neurotrophic factor (BDNF) has previously been associated with a reduction in recognition memory performance. While previous findings have highlighted that this SNP contributes to recognition memory, little is known about its influence on subprocesses of recognition, familiarity and recollection. Previous research has reported reduced hippocampal volume and decreased fractional anisotropy in carriers of the Met allele across a range of white matter tracts, including those networks that may support recognition memory. Here, in a sample of 61 healthy young adults, we used a source memory task to measure accuracy on each recognition subprocess, in order to determine whether the Val66Met SNP (rs6265) influences these equally. Additionally, we compared grey matter volume between these groups for structures that underpin familiarity and recollection separately. Finally, we used probabilistic tractography to reconstruct tracts that subserve each of these two recognition systems. Behaviourally, we found group differences on the familiarity measure, but not on recollection. However, we did not find any group difference on grey- or white-matter structures. Together, these results suggest a functional influence of the Val66Met SNP that is independent of coarse structural changes, and nuance previous research highlighting the relationship between BDNF, brain structure, and behaviour., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The development of fluent reading is an extended process that requires the recruitment of a comprehensive system of perisylvian brain regions connected by an extensive network of fiber pathways. In the present cross-sectional study, we focused on fiber pathways-the arcuate fasciculus (AF), inferior longitudinal fasciculus (ILF), inferior fronto-occipital fasciculus (IFOF), and vertical occipital fasciculus (VOF)-proposed to support early literacy in typical 5-8-year-old children. We related quantitative metrics of fiber pathway microstructure in these pathways to early literacy measures of phonological awareness and decoding. We found that diffusion properties of the AF, ILF, and VOF not only show age-related differences, but also are predictive of early literacy skills after controlling for the effects of age, general white matter development, sex, IQ, and phonological skill. Perhaps most novel, we provide evidence supporting the involvement of the recently re-identified VOF in early literacy, and further, we provide evidence that a bilateral network of fiber pathways supports early literacy development., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Functional magnetic resonance imaging (fMRI) is now capable of sub-millimetre scale measurements over the entire human brain, however with such high resolutions each voxel is influenced by the local fine-scale details of the cerebral cortical vascular anatomy. The cortical vasculature is structured with the pial vessels lying tangentially along the grey matter surface, intracortical diving arterioles and ascending venules running perpendicularly to the surface, and a randomly oriented capillary network within the parenchyma. It is well-known that the amplitude of the blood-oxygenation level dependent (BOLD) signal emanating from a vessel depends on its orientation relative to the B 0 -field. Thus the vascular geometric hierarchy will impart an orientation dependence to the BOLD signal amplitudes and amplitude differences due to orientation differences constitute a bias for interpreting neuronal activity. Here, we demonstrate a clear effect of cortical orientation to B 0 in the resting-state BOLD-fMRI amplitude (quantified as the coefficient of temporal signal variation) for 1.1 mm isotropic data at 7T and 2 mm isotropic at 3T. The maximum bias, i.e. the fluctuation amplitude difference between regions where cortex is perpendicular to vs. parallel to B 0 , is about +70% at the pial surface at 7T and +11% at 3T. The B 0 orientation bias declines with cortical depth, becomes progressively smaller closer to the white matter surface, but then increases again to a local maximum within the white matter just beneath the cortical grey matter, suggesting a distinct tangential network of white matter vessels that also generate a BOLD orientation effect. We further found significant (negative) biases with the cortex orientation to the anterior-posterior anatomical axis of the head: a maximum negative bias of about -30% at the pial surface at 7T and about -13% at 3T. The amount of signal variance explained by the low frequency drift, motion and the respiratory cycle also showed a cortical orientation dependence; only the cardiac cycle induced signal variance was independent of cortical orientation, suggesting that the cardiac induced component of the image time-series fluctuations is not related to a significant change in susceptibility. Although these orientation effects represent a signal bias, and are likely to be a nuisance in high-resolution analyses, they may help characterize the vascular influences on candidate fMRI acquisitions and, thereby, may be exploited to improve the neuronal specificity of fMRI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Auditory prediction errors, i.e. the mismatch between predicted, forthcoming auditory sensations and actual sensory input, trigger the detection of surprising auditory events in the environment. Auditory mismatches engage a hierarchical functional network of cortical sources, which are also interconnected by auditory white matter pathways. Hence it is plausible that these structural and functional networks are quantitatively related. The present study set out to investigate whether structural connectivity of auditory white matter pathways enables the effective connectivity underpinning auditory mismatch responses. Participants (N = 89) underwent diffusion weighted magnetic resonance imaging (MRI) and electroencephalographic (EEG) recordings. Anatomically-constrained tractography was used to extract auditory white matter pathways, namely the bilateral arcuate fasciculi, inferior fronto-occipital fasciculi (IFOF), and the auditory interhemispheric pathway, from which Apparent Fibre Density (AFD) was calculated. EEG data were recorded in the same participants during a stochastic oddball paradigm, which was used to elicit auditory prediction error responses. Dynamic causal modelling was used to investigate the effective connectivity underlying auditory mismatch responses generated in brain regions interconnected by the above mentioned auditory white matter pathways. Our results showed that brain areas interconnected by all auditory white matter pathways best explained the dynamics of auditory mismatch responses. Furthermore, AFD in the right arcuate fasciculus was significantly associated with the effective connectivity between the cortical regions that lie within it. Taken together, these findings indicate that auditory prediction errors recruit a fronto-temporal network of brain regions that are effectively and structurally connected by auditory white matter pathways., (Copyright © 2019 Elsevier Inc. All rights reserved.)